Sulodexide oral administration influences blood viscosity and fibrinolysis.

The aim of this study was to verify the effects of oral administration of a new enteric-coated formulation of sulodexide on blood viscosity and fibrinolysis. Six outpatients suffering from peripheral artery occlusive disease were administered orally two enteric-coated tablets containing 50 mg of sulodexide, twice daily for seven days. On the first and seventh administration days, the following parameters were evaluated: plasminogen activator inhibitor (PAI-1) activity, PAI-1 antigen, tissue plasminogen activator (t-PA) and whole blood, serum and plasma viscosity, before (0 time) and 2, 4 and 8 hours after ingestion of the drug. Following the first administration (50 mg), a slight reduction of PAI was registered; after 7 days' administration, a clear-cut lowering of functional and antigenic PAI was observed, together with an increase of t-PA. As to the drug's influence on blood viscosity, after 7 days the most evident reduction was that registered for plasma viscosity. No side effects were observed throughout the treatment period.     

Sulodexide in the Treatment of Chronic Venous Disease

Chronic venous disease encompasses a range of venous disorders, including those involving the lower limbs resulting from venous hypertension. The spectrum of chronic venous disease signs and symptoms shows variable severity, ranging from mild (aching, pain, and varicose veins) to severe (venous ulcers). The pathophysiology of chronic venous disease is characterized by venous hypertension, which triggers endothelial dysfunction and inflammation leading to microcirculatory and tissue damage, and eventually to varicose veins and venous ulcers. Sulodexide is an orally active mixture of glycosaminoglycan (GAG) polysaccharides with established antithrombotic and profibrinolytic activity. The agent is used in the treatment of a number of vascular disorders with increased risk of thrombosis, including intermittent claudication, peripheral arterial occlusive disease and post-myocardial infarction. Sulodexide differs from heparin because it is orally bioavailable and has a longer half-life and a smaller effect on systemic clotting and bleeding. An increasing body of preclinical evidence shows that sulodexide also exerts anti-inflammatory, endothelial-protective, and pleiotropic effects, supporting its potential efficacy in the treatment of chronic venous disease. Clinical studies of sulodexide have shown that the agent is associated with significant improvements in the clinical signs and symptoms of venous ulcers, and is therefore a recommended therapy in combination with local wound care and bandages for patients with persistent venous leg ulcers. Preliminary evidence supports the use of sulodexide in the prevention of recurrent deep venous thrombosis. Sulodexide was generally safe and well tolerated in clinical trials, without hemorrhagic complications. Sulodexide therefore appears to be a favorable option for the treatment of all stages of chronic venous disease and for the prevention of disease progression.     

Sulodexide: a renewed interest in this glycosaminoglycan

Glycosaminoglycans (GAGs) are the most abundant group of heteropolysaccharides found in the body. These long unbranched molecules contain a repeating disaccharide unit. GAGs are located primarily in the extracellular matrix or on the surface of cells. These molecules serve as lubricants in the joints while at the same time providing structural rigidity to cells. Sulodexide is a highly purified glycosaminoglycan composed of a fast mobility heparin fraction as well as dermatan sulfate. Sulodexide differs from other glycosaminoglycans, like heparin, by having a longer half-life and a reduced effect on systemic clotting and bleeding. In addition, sulodexide demonstrates a lipolytic activity that is increased in comparison to heparin. Oral administration of sulodexide results in the release of tissue plasminogen activator and an increase in fibrinolytic activities. An increasing body of research has demonstrated the safety and efficacy of sulodexide in a wide range of vascular pathologies.     

Sulodexide induces hepatocyte growth factor release in humans

Heparin influences numerous pleiotropic growth factors, including hepatocyte growth factor (HGF), partially by their release from endothelial and extracellular matrix stores. The effects of sulodexide, a heparin-like glycosaminoglycan medication of growing importance in medicine, on HGF liberation are not known. We performed a 2-week open-label sulodexide trial in healthy male volunteers. The drug was initially administered intravenously (i.v.) in a single dose of 1200 Lipoprotein Lipase Releasing Units (LRU), then -- orally for 12 days (500 LRU twice a day), and -- again by i.v. route (1200 LRU) on day 14. Intravenous sulodexide injections were repeatedly found to induce marked and reproducible increases in immunoreactive plasma HGF levels (more than 3500% vs baseline after 10 min, and more than 1200% after 120 min), and remained unchanged when measured 120 min following oral sulodexide administration. The percentage increments in plasma HGF evoked by i.v. sulodexide at both time points and on both days inversely correlated with baseline levels of the growth factor. On day 14, the HGF levels after 120 min and their percentage increase vs baseline were strongly and directly dependent on i.v. sulodexide dose per kg of body weight. This study shows that sulodexide has a novel, remarkable and plausibly biologically important stimulating effect on the release of pleiotropic hepatocyte growth factor in humans.     

Sulodexide prevents peripheral nerve damage in streptozotocin induced diabetic rats

We investigated whether sulodexide has additional protective effects against peripheral nerve damage caused by microvascular dysfunction in a rat model of diabetes. Female Sprague-Dawley (SD) rats were divided into the following 4 groups (n=7-9/group): Normal, Normal+Sulodexide (sulodexide 10mg/kg), diabetic group, and diabetic+Sulodexide (sulodexide 10mg/kg). We assessed current perception threshold, skin blood flow, superoxide dismutase, and proteinuria in experimental rats after oral administration of sulodexide for 20 weeks. We also performed morphometric analysis of sciatic nerves and intraepidermal nerve fibers of the foot. Superoxide dismutase activity in the blood and sciatic nerve were increased significantly after sulodexide treatment in the diabetic group. Current perception threshold was reduced at 2000 Hz (633.3 ± 24.15 vs 741.2 ± 23.5 μA, P<0.05) and skin blood flow was improved (10.90 ± 0.67 vs 8.85 ± 0.49 TPU, P<0.05) in the diabetic+Sulodexide group compared with the diabetic group. The mean myelinated axon area was significantly larger (56.6 ± 2.2 vs 49.8 ± 2.7 μm(2), P<0.05) and the intraepidermal nerve fiber density was significantly less reduced (6.27 ± 0.24 vs 5.40 ± 0.25/mm, P<0.05) in the diabetic+Sulodexide group compared to the diabetic group. Our results demonstrate that sulodexide exhibits protective effects against peripheral nerve damage in a rat experimental model of diabetes. Therefore, these findings suggest that sulodexide is a potential new therapeutic agent for diabetic peripheral neuropathy.     

舒洛地特联合缬沙坦对早期糖尿病肾病疗效临床研究

目的:观察舒洛地特联合缬沙坦对早期糖尿病肾病的疗效.方法:将我院就诊的早期DN患者60例,随机分为对照组和治疗组,两组同时给予常规综合治疗.对照组给予缬沙坦80mg口服,每日1次,共7周;治疗组在此基础上加用舒洛地特600LSU肌注,每日1次,15天后改为250LSU口服,每日两次,总疗程7周.检测两组患者在治疗前后的...     

舒洛地特治疗糖尿病肾病Ⅲ期的疗效研究

目的研究舒洛地特对治疗2型糖尿病肾病Ⅲ期尿微量白蛋白排泌率(UAER)的疗效。方法 93例糖尿病肾病Ⅲ期患者被随机分为三组,常规组29组,舒洛地特组33例,福辛普利组31例。疗程均为8周。结果治疗8周后,舒洛地特组UAER(63.54±23.39)μg/min较正常组(110.74±37.52)μg/min相比,有显著统计学意义(P<0.001);较福辛普利组(69.56±21.47)μg/min相比,无统计学意义(P>0.05)。结论舒洛地特可有效降低2型糖尿病肾病Ⅲ期患者的尿微量蛋白排泌率。     

舒洛地特加替米沙坦对2型糖尿病视网膜病变疗效观察

目的通过舒洛地特联合替米沙坦对2型糖尿病视网膜病变（diabeticretinopathy，DR）减少眼底微动脉瘤、延缓DR进展速度有效性的观察，评价舒洛地特和替米沙坦联合应用对DR的疗效。方法162例DR患者随机分为三组，替米沙坦组、舒洛地特组和联合治疗组，所有患者随访6个月，随访过程中定期检查眼底，空腹血糖、糖化血红蛋白、谷丙转氨酶、谷草转氨酶、纤维蛋白原。结果三组患者眼底微动脉瘤治疗后较治疗前均明显较少，差异有统计学意义（P〈0．05），治疗后三组间患者眼底微动脉瘤比较，差异无统计学意义（P〉0．05），联合治疗组与替米沙坦组、舒洛地特组相比，可延缓DR增殖型进展速度，差异有统计学意义（P〈0．05）。结论舒洛地特联合替米沙坦治疗DR能有效减少眼底微动脉瘤、延缓DR进展速度，疗效优于单一治疗组。     

舒洛地特对老龄糖尿病大鼠足细胞的保护作用

目的 探讨舒洛地特对老龄糖尿病大鼠足细胞的保护作用. 方法20个月龄SD大鼠制备链脲佐菌素（STZ）糖尿病模型后,随机分为糖尿病组和舒洛地特治疗组,另设对照组. 于4,8周末收集大鼠24 h尿,监测血压. 8周后处死大鼠,行组织病理学检查,检测24 h尿清蛋白、血肌酐、尿肌酐和肌酐清除率（Ccr）,应用免疫组化检测肾小球结蛋白表达. 结果 老龄糖尿病大鼠24 h的尿总蛋白、血压明显高于对照组（P<0.05）,且出现较为明显的病理学损害. 肾小球中结蛋白表达较对照组显著增加. 尿清蛋白程度与结蛋白表达成显著正相关（P<0.05）. 舒洛地特可明显减轻肾脏病理损害,降低结蛋白表达,减少尿清蛋白排泄. 结论 老龄糖尿病大鼠出现足细胞损伤,导致尿清蛋白排泄增加. 舒洛地特可以纠正这些改变,对足细胞损伤起保护作用.     

舒洛地特治疗2型糖尿病早期肾病的临床观察

目的：观察舒洛地特对2型糖尿病早期肾病的治疗作用。方法：144例不伴高血压的2型糖尿病早期肾病患者,代谢控制稳定后,原糖尿病治疗方案不变,随机分为常规治疗组、舒洛地特治疗组、苯那普利治疗组及舒洛地特＋苯那普利治疗组。观察治疗前、治疗4周、治疗12周,尿白蛋白/尿肌酐（ACR）的变化,同时观察空腹血糖、糖化血红蛋白、血总胆固醇、血甘油三酯、血肌酐、纤维蛋白原的变化。结果：除常规治疗组外,其他三组治疗12周前后的ACR比较均有统计学差异（P〈0.01）。治疗12周后,舒洛地特治疗组、苯那普利治疗组、舒洛地特＋苯那普利治疗组与常规治疗12周后相比,ACR下降有统计学差异（P〈0.01）,但3组间治疗后12周的差异无统计学意义（P〉0.05）。结论：舒洛地特能减少2型糖尿病早期肾病的ACR,延缓肾病的进展,是一种新的治疗糖尿病肾病的途径。     

肾炎康复片联合舒洛地特治疗早期慢性肾脏病观察

摘 要 目的： 观察肾炎康复片联合舒洛地特治疗早期慢性肾脏病（CKD）的效果。方法: 88例早期慢性肾脏病患者随机分为2组,对照组给予低盐低脂低蛋白饮食,常规基础治疗（ACEI或ARB）、控制血糖、对症等治疗,观察组在对照组基础上加服肾炎康复片2.4 g,po,tid, 舒洛地特250 LSU/次,bid,疗程4个月,每2个月监测24h尿蛋白定量、尿红细胞(URBC)、尿白蛋白排泄率、尿N-乙酰-β-D-葡萄糖苷酶（NAG）、C-反应蛋白(CRP),β2-微球蛋白（β2-MG）、肾小球滤过率（GFR）、肝功、血脂、血糖等指标。结果: 2组治疗4个月后24 h尿蛋白定量、URBC、尿白蛋白排泄率、NAG、CRP、β2-MG和GFR等指标均较治疗前明显好转(P<0.05或P<0.01),且观察组上述指标均明显优于对照组(P<0.05)。结论:肾炎康复片联合舒洛地特能延缓早期CKD的进展。     

多糖类抗血栓药物舒洛地特与低分子肝素的多方位比较分析

目的：舒洛地特与低分子肝素都是多糖类抗血栓药物,多方位比较二者的异同,对监管提出建议。方法：从构效关系入手,探讨质控基本要求,对作用机理、临床应用、不良反应等多方位进行全面梳理并比较二者的抗凝、抗血栓强度及临床应用价值。结果与结论：舒洛地特与低分子肝素作为抗血栓药物,二者抗血栓作用相当,抗凝作用舒洛地特比低分子肝素强,并且无出血风险。由于多组分多糖类药物质量控制难度较大,本文提出对原料药和制剂的监管需要从起始物料源头开始,参照生物类似药进行生产全过程质量控制,以保证多糖类药物的质量稳定、安全有效。     

Mechanism of the microcirculatory effects of ethyl-3,5,6-tri-O-benzyl-D-glucofuranoside

According to the rheo- and photoplethysmography data, ethyl-3,5,6-tri-O-benzyl-D-glucofuranoside (glivenol, tribenol; 25,250 and 4000 mg/kg i.p.) markedly increases the blood content in hind limbs of rabbits, displaying a tendency towards a decrease in systemic arterial pressure and negligibly raises the body temperature when given in maximal doses, without affecting cardiac activity and respiration. The mechanism of the drug hemodynamic effect revealed is determined by activation of the blood flow in precapillary vessels. This plays an essential role in pathogenetic therapy of microcirculatory and trophic disorders in chronic venous failure.     

坎地沙坦联合舒洛地特软胶囊治疗糖尿病肾病持续蛋白尿的疗效观察

目的:观察坎地沙坦联合舒洛地特软胶囊治疗糖尿病肾病持续蛋白尿的疗效。方法:选取糖尿病肾病持续蛋白尿期患者180例,按随机数字表法分为对照组和试验组,各90例。对照组患者采用坎地沙坦治疗,8 mg/次,1次/d;试验组患者在对照组基础上加用舒洛地特软胶囊,250 LSU/次,2次/d。观察两组患者治疗前后收缩压(SBP)、舒张压(DBP)、血肌酐(Scr)、血尿素氮(BUN)、尿白蛋白排泄率(UAER)、24 h尿微量白蛋白(24h U-Alb)、尿β2-微球蛋白(β2-MG)、α1-微球蛋白(α1-MG)、尿N-乙酰-β-D葡萄糖苷酶(NAG)及血清胱抑素C(Cys-C)等指标水平。结果:治疗后,两组患者SBP、DBP、Scr、BUN、UAER水平比较,差异无统计学意义(P>0.05);试验组患者24h U-Alb水平显著优于对照组,差异有统计学意义(P<0.05);治疗后,两组患者β2-MG、α1-MG、NAG、Cys-C较治疗前均显著改善,且试验组患者改善优于对照组,差异有统计学意义(P<0.05)。结论:坎地沙坦联合舒洛地特软胶囊用于糖尿病肾病持续蛋白尿期可有效改善患者肾脏功能,降低U-Alb量。     

The involvement of endothelial dysfunction, nitric oxide and prostanoids in the rat gastric microcirculatory responses to endothelin-1.

1. The role of endothelial dysfunction in the gastric microcirculatory responses during local endothelin-1 (ET-1) infusion has been investigated in the pentobarbitone-anaesthetized rat. Furthermore, the involvement of prostanoids or nitric oxide (NO) in these actions has been investigated by the use of indomethacin to inhibit cyclo-oxygenase and NG-nitro-L-arginine methyl ester (L-NAME) to inhibit NO synthase. 2. Close-arterial infusion of ET-1 (1-10 pmol kg-1 min-1 for 10 min) induced a dose-dependent increase in the gastric leakage of radiolabelled albumin, used as an index of endothelial cell dysfunction. 3. Close-arterial infusion of a submaximal dose of ET-1 (5 pmol kg-1 min-1 for 10 min) significantly increased gastric albumin leakage after 2 min infusion, which reached maximal levels after 10 min, and only slowly declined during the 30 min observation period. 4. By contrast, gastric blood flow, as assessed by laser Doppler flowmetry, did not significantly increase until after 5 min of infusion of ET-1 (5 pmol kg-1 min-1 for 10 min), reaching a maximum after 17 min, and was sustained for the 30 min observation period. 5. Pretreatment with L-NAME (2 mg kg-1, i.v.) or indomethacin (5 mg kg-1, i.v.) significantly reduced both the hyperaemic response to ET-1 and the increase in gastric albumin leakage, and in combination abolished these responses. 6. These results suggest that locally released NO and prostanoids mediate the gastric vasodilator response to close arterial infusion of ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

气功对急性高原低氧时微循环障碍的影响及其机理

我们对300名世居平原青年随机分为气功组、体育组和党参组，分别在进藏8周前对气功组和体育组进行启元气功和广播体操锻炼，党参组于进藏前3天口服复方党参片，直至进藏后第5天止。进藏前对上述3组进行测量血压、左手劳宫穴温度测定及舌尖、甲襞微循环检查。从结果可看出气功具有改善急性高原缺氧所致的微循环障碍，通过调动人体的潜能，对自身微循环功能的调整平衡作用，来减低高原缺氧带来的各种症状，加速机体对高原缺氧的适应能力和缩短了习服时间。我们认为气功是一种省时、经济方便，易于在大部队推广的锻炼方法。     

Dronedarone prevents microcirculatory abnormalities in the left ventricle during atrial tachypacing in pigs

BACKGROUND AND PURPOSE

Atrial fibrillation induces ischaemic microcirculatory flow abnormalities in the ventricle, contributing to the risk for acute coronary syndromes. We evaluated the effect of dronedarone on ventricular perfusion during rapid atrial pacing (RAP).

EXPERIMENTAL APPROACH

Coronary and fractional flow reserve (CFR/FFR) were measured in the left anterior descending artery in 29 pigs. Six received RAP, six received RAP with dronedarone (RAP/D), seven received dronedarone alone, four received RAP with amiodarone (RAP/A), and six received neither (sham). In ventricular tissue, oxidative stress/ischaemia-related gene and protein expression was evaluated by RT-PCR and Western blotting; Isoprostanes were measured by GC-MS procedures.

KEY RESULTS

CFR was decreased in the RAP group, compared with other groups. FFR was not different between groups. Effective refractory period was reduced in RAP compared with RAP/D. RAP-activated PKC phosphorylation tended to be decreased by dronedarone (P= 0.055) RAP induced NOX-1 and NOX-2 protein and the mRNA for hypoxia-inducible factor-1α (HIF-1α). Dronedarone reduced the pacing-dependent increase in the expression of NOX-2 protein and of HIF-1α mRNA. The oxidative stress marker, F₂-isoprostane, was increased by RAP and this increase was attenuated by dronedarone. Other oxidative stress/ischaemia-related genes were induced by RAP compared with sham and were decreased by dronedarone treatment. In HL1 cells, dronedarone significantly inhibited the increased phosphorylation of PKCα after oxidative stress, with an almost significant effect (P= 0.059) on that after RAP.

CONCLUSIONS AND IMPLICATIONS

Dronedarone abolished RAP-induced ventricular microcirculatory abnormalities by decreasing oxidative stress/ischaemia-related gene and protein expression in the ventricle.